Drug-Induced Aseptic Meningitis: A 25-Year Systematic Review of Case Reports.

Several drugs can induce the development of aseptic meningitis. Drug-induced aseptic meningitis (DIAM) can mimic an infectious process as well as meningitides that are secondary to systemic disorders for which these drugs are used. Thus, DIAM constitutes a diagnostic and patient management challenge. Cases of DIAM were reviewed through a MEDLINE literature search (up to June 1998) to identify possible clinical and laboratory characteristics that would be helpful in distinguishing DIAM from other forms of meningitis or in identifying a specific drug as the culprit of DIAM. Our review showed that nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, intravenous immunoglobulins, and OKT3 antibodies (monoclonal antibodies against the T3 receptor) are the most frequent cause of DIAM. Resolution occurs several days after drug discontinuation and the clinical and cerebrospinal fluid profile (neutrophilic pleocytosis) do not allow DIAM to be distinguished from infectious meningitis. Nor are there any specific characteristics associated with a specific drug. Systemic lupus erythematosus seems to predispose to NSAID-related meningitis. We conclude that a thorough history on prior drug intake must be conducted in every case of meningitis, with special focus on those aforementioned drugs. If there is a suspicion of DIAM, a third-generation cephalosporin seems a reasonable treatment option until cerebrospinal fluid cultures are available.

Drug-induced aseptic meningitis (DIAM) has been reported as an uncommon adverse reaction with numerous agents. It is a diagnosis of exclusion, and clinical signs and CSF findings vary greatly. The body of evidence regarding DIAM is largely in the form of anecdotal case reports and must be interpreted carefully bearing this in mind. The major categories of causative agents are nonsteroidal anti-inflammatory drugs, antimicrobials, intravenous immunoglobulin, intrathecal agents, vaccines and a number of other less frequently reported agents. There appears to be an association between DIAM and connective tissue disease, particularly systemic lupus erythematosus, and ibuprofen. There are 2 major proposed mechanisms for DIAM. The first involves direct irritation of the meninges by intrathecal administration of the drug, and the second involves immunological hypersensitivity to the drug, most likely type III and type IV hypersensitivity. Recognition and diagnosis of DIAM is important, as it is treatable by withdrawal of the drug and recurrence is prevented. The outcome of DIAM is generally good, usually without long term sequelae. This article describes the case reports of DIAM in the current literature and discusses the diagnosis and management of this rare complication.

Drug-induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify suspected drugs. Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All cases were initially analysed according to the French imputability method by institutional pharmacologists (clinicians or pharmacists). Further analyses of well documented cases were then performed. In this study, 329 cases of aseptic meningitis were retrieved from the French Pharmacovigilance Database for a total of 429 suspected drugs. Analysis of 203 well documented cases, including 282 drugs, showed that the main reported classes were intravenous polyvalent immunoglobulin, nonsteroidal anti-inflammatory drugs (NSAIDs), vaccines, antimicrobials, intrathecal antimetabolites, corticosteroids and antalgics/anaesthetics (except NSAIDs). Lymphocytic (33.0%) and purulent (44.8%) meningitis represented the majority of cases of aseptic meningitis. In other cases, the cerebrospinal fluid was mixed (45-55% of neutrophils +45-55% of lymphocytes) or data about cerebrospinal fluid composition were lacking. Most DIAM cases (96%) had a favourable reported outcome with full recovery or minimal residual symptoms. The most frequently involved drugs in DIAM were intravenous polyvalent immunoglobulin, NSAIDs, vaccines, and antimicrobials and this without being able to differentiate them in terms of biological characteristics. Although further studies are needed to better understand the pathophysiological mechanisms of DIAM, a continuous enrichment of pharmacovigilance databases is essential to identify new signals and to help clinicians in the understanding of DIAM.

Drug-induced meningitis: A review of the literature and comparison with an historical cohort of viral meningitis cases

Méningite aseptique induite par L’allopurinol

Meningitis causes inflammation of the meninges and when bacteria are not the cause may be considered aseptic. Drug-induced aseptic meningitis (DIAM) can arise from the use of certain medications. The pathophysiology of DIAM is not well understood. Within the antiepileptic medication class, only lamotrigine, carbamazepine, and levetiracetam have been associated with DIAM via documented cases. Common presentation of DIAM involves fever, headache, meningismus, and mental status changes (abnormal consciousness and focal neurological deficits). Other clinical features may include neck stiffness, photophobia, nausea, vomiting, abdominal pain, bone pain, hypotension, edema (facial and optic nerve), rash, and seizures. Case reports of DIAM with varying or limited symptomology exist. Therefore, the presentation alone will not allow for a DIAM diagnosis, prompting further analysis and diagnostic exclusion. A middle-aged male presented with a 48-hour history of confusion, disorientation, unresponsiveness, and hypersomnolence. Past medical history included hypertension, hyperlipidemia, type-2 diabetes, and seizures. Home medication included chlorthalidone, levetiracetam, lisinopril, metformin, potassium chloride, rosuvastatin with no medication allergies reported. Upon admission, the patient denied fever, headache, nausea, neck pain, vomiting, and rash. Somnolence, dysarthria, and obtundation were noted during the physical evaluation. Hospital medications included home medications along with enoxaparin, correctional dose insulin lispro, and IV lactated ringers. Vitals and labs were unremarkable. On hospital day (HD) 1 the MRI scan was unremarkable, ruling out a demyelinating process. Serology tests (ie, ANA and dsANA) were negative. Neurology was consulted, and a lumbar puncture was performed. On HD-2 AEIM was suspected, prompting levetiracetam discontinuation and lacosamide initiation (50mg by mouth twice daily). The CSF analysis was notable for pleocytosis (lymphocytic predominance at 96%), elevated protein (100mg/dL), and slightly elevated glucose (79mg/dL). The CSF VDRL was negative, ruling out neurosyphilis. Bacterial meningitis was ruled out based on the CSF analysis (WBC 144×103 and glucose) and the lack of bacterial growth on gram stain. Inasmuch, antibiotic therapy was not initiated. Empiric acyclovir 1000mg IV every 8hours was initiated as viral meningitis had not been eliminated, due to the lack of viral meningeal PCR testing. By HD-3, the CSF culture resulted without growth and the patient was alert and oriented. By HD-4 the patient was discharged, having received 6 doses of IV acyclovir, with 7 more days of oral therapy. In 2018, McDonald et al documented the first case of probable levetiracetam-related antiepileptic induced meningitis (AEIM). The mainstay of treatment is discontinuing the offending agent. Resolution of symptoms is typically 2 to 3days after drug discontinuation as seen in this patient case report. Symptomatic resolution within days of stopping the suspected offending drug has been observed in all reported cases of AEIM where 1 to 2 weeks is generally seen with viral meningitis. Applying the Naranjo Scale yields a score of 4, which indicates possible levetiracetam-induced meningitis in this adult patient. Providers should be cognizant when prescribing antiepileptics to assess and monitor for aseptic meningitis that may appear with atypical symptoms. No funding.

Aseptic meningitis is a rare but well-recognized complication of drug therapy. The clinical presentation of drug-induced aseptic meningitis (DIAM) is distinct. Symptoms typically include fever, neck stiffness, headache, confusion, nausea and vomiting. The major categories of causative agents are non-steroidal anti-inflammatory drugs, antimicrobials and also intravenous immunoglobulins, monoclonal antibodies and vaccines. These drugs most commonly implicated as causes of aseptic meningitis act more likely through an immunological mechanisms. However, the exact pathogenetic mechanism of DIAM is still unknown. The diagnosis of drug-induced aseptic meningitis is difficult and infectious etiologies must be excluded. In some cases the diagnosis has been confirmed by rechallenging the patient with the suspected agent. In this case, informed written consent is necessary and rechallenge must be medically supervised both to document the response and to offer medical care and advice, if required. The outcome of DIAM is generally good, usually without long term sequelae.

Drug-induced aseptic meningitis in suspected central nervous system infections

Drug-associated headache is a quite common phenomenon, e.g. as a side effect of distinct substances such as nitric oxide or as a result of medication overuse of analgesic drugs. A different drug-associated headache entity is headache in drug-induced aseptic meningitis (DIAM). This is a rare disorder and only described in few case reports or smaller case series. One of the main clinical features of DIAM despite fever is headache. Based on the literature, no typical or even pathognomonical clinical presentation of this headache entity can be described. Sometimes, migrainous features might be present, and treatment response to triptans was reported in single case reports. Headache in DIAM seems to be emerging from sterile meningeal inflammation, which is suggested to represent the underlying pathology in DIAM. Headache in DIAM usually ceases when treated sufficiently, mainly through termination or withdrawal of the causing agent. Migraine as a predisposing factor of DIAM has been discussed previously but remains unproven.

Recurrent Severe Aseptic Meningitis after Exposure to Lamotrigine in a Patient with Systemic Lupus Erythematosus

Drug-induced aseptic meningitis (DIAM) is a noninfectious meningitis related to a drug exposure. Diagnosis requires exclusion of infectious meningitis. Patients with DIAM will exhibit rapid improvement after discontinuation of the offending drug. Most patients will develop recurrent symptoms after repeat exposure to the offending agent. The clinical features of DIAM are indistinguishable from infectious meningitis and the recurrent symptoms often are identical to previous episodes of DIAM. Nonsteroidal anti-inflammatory drugs, co-trimoxazole, and penicillin are the medications that most commonly cause DIAM with use. This article describes a patient who was admitted to the hospital with meningoencephalitis after taking prophylactic amoxicillin for a dental procedure.

Drug-induced aseptic meningitis (DIAM) is a rare but clinically important adverse event. We identified drugs potentially associated with aseptic meningitis using the Japanese Adverse Drug Event Report (JADER) database. We conducted a disproportionality analysis of aseptic meningitis adverse events using JADER data from April 2004 to October 2024. Disproportionality signals for aseptic meningitis were detected using reporting odds ratios (RORs) with 95% confidence intervals. The Weibull distribution was analyzed to evaluate the time to onset of adverse events for drugs producing symptoms of aseptic meningitis. Nineteen drugs were identified as associated with aseptic meningitis: nine vaccines, three immunoglobulin products, two nonsteroidal anti-inflammatory drugs, and two immune checkpoint inhibitors (nivolumab and ipilimumab), among others. The onset of DIAM temporally associated with the SARS-CoV-2 RNA vaccine was typically observed within a few days following vaccination, resembling the temporal pattern reported for conventional DIAM. In contrast, the DIAM onset after nivolumab and ipilimumab treatment was delayed, leading to the classification of these drugs as random failure types, which is consistent with the timing of the immune-related adverse events. DIAM onset patterns differ among therapeutic classes, including immune checkpoint inhibitors and SARS-CoV-2 RNA vaccines. These differences in onset timing suggest that DIAM onset occurs through distinct pathophysiological mechanisms. This information may support differential diagnosis and guide management of aseptic meningitis in clinical settings.

Drug-induced aseptic meningitis (DIAM) mainly occurs with nonsteroidal anti-inflammatory drugs (NSAID), antibiotics, IV immunoglobulins, anti-CD3 monoclonal antibodies, intrathecal agents, and vaccines.1,2⇓ Systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) are the most frequent underlying conditions associated with DIAM, especially when caused by NSAIDs.1,2⇓ We report a case of pentoxifylline-induced aseptic meningitis in a patient with MCTD. A 37-year-old Lebanese woman had a 16-year history of MCTD with Raynaud’s phenomenon, distal inflammatory arthralgias, neutropenia, lymphopenia, positive erythrocyte Coombs’ test, high speckled antinuclear antibodies, anti-SSA, high anti-RNP, and no anti–double-stranded DNA (dsDNA) antibodies. She was prescribed hydroxychloroquine. At the age of 34, chilblain lupus affected fingers, and anti-dsDNA antibodies were detected. Thalidomide was given with the hydroxychloroquine but rapidly stopped due to the occurrence of high fever, chills, arthralgias, and rash. She completely recovered after thalidomide discontinuation. One year later, because of Raynaud’s phenomenon, pentoxifylline was started …

There have been several local and systemic adverse events associated with mRNA COVID-19 vaccines. Pericarditis, myocarditis and myocardial infarction are examples of cardiac complications related to these vaccines. In this article, we conducted a systematic review of case reports and case series to identify the clinical profile, investigations, and management of reported cardiac complications post-mRNA COVID-19 vaccines. We systematically searched PubMed, Scopus, Web of Science, and Google Scholar, as well as the medRxiv preprint server, with terms including: 'SARS-CoV-2', 'COVID-19', 'messenger RNA vaccine*', 'mRNA-1273 vaccine', 'BNT162 vaccine', 'myocarditis', 'pericarditis', 'stroke' and 'Myocardial Ischemia' up to 25 September 2021. Studies were excluded if they were not case reports or case series, or reported cases from non-mRNA vaccines. Case reports and case series were included that investigated the potential cardiac complications associated with mRNA COVID-19 vaccines. The JBI checklist was used to assess quality and data synthesis was conducted using a qualitative methodology called narrative synthesis. Sixty-nine studies, including 43 case reports and 26 case series, were included. Myocarditis/myopericarditis and pericarditis were the most common adverse events among the 243 reported cardiac complications, post mRNA COVID-19 vaccination. Males with a median age of 21years had the highest frequency of myocarditis. Almost three quarters (74.4%) of cases with myocarditis had received the BNT162b2 vaccine and 87.7% had received the second dose of the vaccine. Chest pain (96.1%) and fever (38.2%) were the most common presentations. CK-MB, troponin, and NT-proBNP were elevated in 100%, 99.5% and 78.3% of subjects, respectively. ST-segment abnormality was the most common electrocardiogram feature. Cardiac magnetic resonance imaging, which is the gold-standard approach for diagnosing myocarditis, was abnormal in all patients diagnosed with myocarditis. Non-steroidal anti-inflammatory drugs were the most prescribed medication for the management of myocarditis. Apart from inflammatory conditions, some rare cases of Takotsubo cardiomyopathy, myocardial infarction, myocardial infarction with non-obstructive coronary arteries, and isolated tachycardia were also reported following immunisation with mRNA COVID-19 vaccines. We acknowledge that only reviewing case reports and case series studies is one potential limitation of our study. We found that myocarditis was the most commonly reported adverse cardiac event associated with mRNA COVID-19 vaccines, which presented as chest pain with a rise in cardiac biomarkers. Further large-scale observational studies are recommended.

Naproxen-induced aseptic meningitis